1. Field of the Invention
The invention relates to the preparation of navelbine and novel analogs and derivatives of navelbine through a de novo synthesis of the nor-catharanthine moiety of the bis-indole vinblastine. Anti-tubulin activity of a navelbine derivative prepared by the novel synthesis is disclosed.
2. Description of Related Art
The synthesis of Vinca plant alkaloids and related compounds is of interest because of the anti-tumor activity of many of these compounds. Vinblastine is the archetype of a class of dimeric alkaloids well-known for the ability to disrupt microtubule formation, the property apparently crucial to its anti-tumor activity. Vinblastine and related compounds have been used for treatment of Hodgkin's disease and ovarian cancer (Lhomme, 1990).
Unfortunately, as with many drugs, in vivo cross resistance of vinca alkaloid drugs often arises (Maral, et al., 1981). Another disadvantage of these drugs is their toxicity, particularly neurotoxicity (Binet et al., 1990). This has stimulated efforts to synthesize analogs of the vinca alkaloids that retain antimitotic activity while showing reduced toxicity.
Total synthesis of vinblastine has not been achieved; however, various non-naturally occurring Vinca alkaloid compounds have been prepared, the most significant of which is navelbine, the nor-anhydro analog of vinblastine. Navelbine is of interest because it has exhibited broader antitumor activity and lower neurotoxicity and other side effects than vinblastine and vincristine (Fellous et al., 1989).
Navelbine has not previously been totally synthesized. Its preparation has been based a two-step reaction from anhydrovinblastine involving N-oxide formation, followed by a Polonovski rearrangement. Two significant disadvantages of this preparation are the inefficiency of the synthesis (Gueritte et al., 1983) and that the preparation of derivatives is limited to reactions that can be run on either the starting bis-alkaloid (vinblastine) or its nor-analog, navelbine.
Consequently, few derivatives of navelbine have been prepared. While relatively simple compounds such as desacetylnavelbine are known, most navelbine-related compounds are limited to straightforward functionalizations across the 5-'4' double bond of navelbine (Langlois et al., 1981). Some of these compounds have varying degrees of antileukemic activity, although none appear significantly superior to the parent compound. There is significant interest and perceived need in developing routes to a wide range of navelbine analogs and related compounds for testing in cancer chemotherapy.